Method of making microneedle array and device for applying microneedle array to skin

ABSTRACT

Microneedle arrays and drug delivery devices are provided for transdermally delivering a drug formulation to a patient. The microneedle array device includes a substantially planar substrate having an array of apertures; and a plurality of microneedles projecting at angle from the planar substrate, the microneedles having a base portion integrally connected to the substrate, a tip end portion distal to the base portion, and body portion therebetween, wherein each microneedle has at least one channel extending substantially from the base portion through at least a part of the body portion, the channel being open along at least part of the body portion and in fluid communication with at least one of the apertures in the substrate. In a preferred embodiment, each microneedle has a substantially rectangular cross-sectional shape and the channel is open to two opposing surfaces of the microneedle.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional of U.S. application Ser. No. 11/328,813, filed Jan.10, 2006, now U.S. Pat. No. 7,658,728, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

This invention is generally in the field of devices for theadministration of drugs to patients through the skin. More particularly,this invention relates to microneedle arrays and methods for transdermaldrug delivery.

Transdermal drug delivery provides several advantages over other routesfor administering a drug formulation to a patient. For example, oraladministration of some drugs may be ineffective because the drug isdestroyed in the gastrointestinal tract or eliminated by the liver, bothof which are avoided by transdermal drug delivery. Parenteral injectionwith a conventional hypodermic needle also has drawbacks, as it is oftenpainful and inconvenient. Although transdermal drug delivery avoidsthese problems, there are obstacles to its use. In particular, thetransport of drug molecules through the intact stratum corneum, theouter layer of the skin, is often quite difficult due to the barrierproperties of the stratum corneum. These barrier properties only allowrelatively small molecules to be transported through the intact stratumcorneum, and many useful drugs are too large to pass through the stratumcorneum without some type of modification of the stratum corneum orother transport enhancement. Various transdermal enhancement methods areknown, including those based on iontophoresis, ultrasound, and chemicalpenetration enhancers. However, these methods may be inadequate toassist in the delivery of many medications through an intact skin layerand/or they may be inconvenient or undesirably complicated to use.

Several methods have been recently proposed for making small pores inthe stratum corneum in order to overcome its barrier properties. Forexample, patents to Altea Therapeutics disclose the use of arrays ofmicro-heaters for creating tiny holes in the stratum corneum, as well asthe use of miniature pyramidal projections to porate the stratumcorneum. See, e.g., U.S. Pat. No. 6,142,939 to Eppstein et al. and U.S.Pat. No. 6,183,434 to Eppstein. Others, including Procter & Gamble, AlzaCorporation, and scientists and engineers at the University ofCalifornia, Berkeley and at the Georgia Institute of Technology, havebeen working on the development of microneedle arrays that would make alarge number of tiny holes in the stratum corneum. See, e.g., U.S. Pat.No. 6,611,707 to Prausnitz et al. and U.S. Pat. No. 6,334,856 to Allenet al.

These known microneedle array generally fall into one of two designcategories: (1) solid microneedles and (2) microneedles with a centralhollow bore, which are similar to conventional hypodermic needle. Solidmicroneedle arrays are essentially arrays of projections that are usedto make holes in the stratum corneum and are subsequently removed beforea drug is applied to the skin. If solid microneedle arrays are kept inthe skin, then the drug cannot readily flow into and through the holesin the skin because the holes remain plugged by the microneedles. In anapparent effort to work around this problem, Alza Corporation disclosesa method of depositing a drug directly on the surface of these solidmicroneedles. However, the deposition process is unreliable, and thethin layer of drug formulation on the microneedle could be easilychipped off of the microneedle during storage, transport, oradministration (insertion) of the microneedles. Moreover, application ofa thicker and stronger layer of drug formulation was found to beundesirable because it reduced the sharpness of the microneedles andtherefore made insertion more difficult and painful. In response to thisdeficiency with the thicker drug coating, Alza Corporation disclosed aspecial insertion device, because patients are unable to insert themicroneedle array by their selves without it. It therefore would bedesirable to provide a microneedle array for drug delivery that avoidsthe disadvantages associated with known solid microneedle array designs.

Conventional hollow microneedles with a central bore are expensive tomake and require exotic and expensive microfabrication methods. Inparticular, it is difficult to make sharp tips on hollow microneedles.Consequently, insertion of the microneedles into a patient's skin can bedifficult and often painful. In addition, the central bore of themicroneedle is quite small and may be easily plugged by skin tissueduring the insertion process, thereby blocking the drug deliveryconduit. Furthermore, because the length of microneedle central bore ismuch greater than its diameter, the diffusional transport of the drugthrough the central bore may be unacceptably slow. It may be even slowerthan the diffusion of the drug through the stratum corneum in theabsence of the microneedle. It therefore would be desirable to provide amicroneedle array for drug delivery that avoids the disadvantagesassociated with known hollow microneedle array designs.

U.S. Patent Application Publication No. 2003/0028125 discloses devicesand methods for piercing the skin and accessing and collecting aphysiological fluid sample therein. The disclosed device is unsuitablefor drug delivery to the stratum corneum, in particular because theneedle design is too large for such applications.

In summary, there is a need for a simple, effective, and economicallydesirable device for transdermal administration of a variety of drugtypes to a patient.

SUMMARY OF THE INVENTION

Microneedle arrays and drug delivery devices incorporating themicroneedle arrays are provided, along with methods of makingmicroneedle arrays and using microneedle arrays and devices to deliver adrug formulation through a biological barrier, such as the stratumcorneum of human skin.

In one aspect, a microneedle array device is provide which includes asubstantially planar substrate having an array of spaced aperturestherein; and a plurality of microneedles projecting at angle from theplane in which the planar substrate lies, the microneedles having a baseportion integrally connected to the substrate, a tip end portion distalto the base portion, and body portion therebetween, wherein at least oneof the microneedles has at least one channel extending substantiallyfrom the base portion through at least a part of the body portion, thechannel being open along at least part of the body portion and in fluidcommunication with at least one of the apertures in the substrate. In apreferred embodiment, the at least one of the microneedles has asubstantially rectangular cross-sectional shape in a plane parallel tothe substrate. In one specific variation of this embodiment, the atleast one channel is open to two opposing surfaces of the microneedle.

In another embodiment, the tip end portion of the at least one of themicroneedles is tapered. In a specific embodiment, the at least onechannel terminates in the body portion of the microneedle and does notextend into the tapered tip portion.

In a preferred embodiment, the substrate and the microneedles compriseat least one biocompatible metal, such as a stainless steel. In anotherembodiment, the substrate and the microneedles comprise at least onebiocompatible polymer.

In one embodiment, the length of the at least one microneedle may bebetween 10 μm and 1000 μm, preferably between 100 μm and 500 μm. Inanother embodiment, the at least one microneedle has a maximum widthdimension of 500 μm.

In one embodiment, the body portion of the at least one microneedle isrectangular with a centrally located channel extending through theopposed longer sides of the body portion. In one particular embodiment,the rectangular body portion has a long side cross-sectional dimensionbetween 1 and 500 μm and a short side cross-sectional dimension between1 and 200 μm.

In one embodiment, the apertures in the substrate are polygonal inshape, each aperture being defined by three or more interior sidesurfaces in the substrate. In one embodiment, the base portion of the atleast one microneedle includes a curved portion that extends from atleast one of the interior side surfaces of the substrate. In oneembodiment, a proximal end of the at least one channel extends to orinto the at least one of the interior side surfaces of the substrate.

In another aspect, a device for transdermal administration of a drug isprovided, which includes a substantially planar substrate having anarray of spaced apertures therein; a plurality of microneedlesprojecting at angle from the plane in which the planar substrate lies,the microneedles having a base portion integrally connected to thesubstrate, a tip end portion distal to the base portion, and bodyportion therebetween, wherein at least one of the microneedles has atleast one channel extending substantially from the base portion throughat least a part of the body portion, the channel being open along atleast part of the body portion and in fluid communication with at leastone of the apertures in the substrate; and at least one drug storageelement, which contains a drug formulation, positioned adjacent to theplanar substrate. In a preferred embodiment, the at least one of themicroneedles has a substantially rectangular cross-sectional shape in aplane parallel to the substrate. The at least one channel may be open totwo opposing surfaces of the microneedle.

In one embodiment, the drug storage element is attached to a firstsurface of the planar substrate, the first surface being opposed to asecond surface of the planar substrate of the microneedle array, whereinthe microneedles project from the second surface.

In another embodiment, the device further includes a release mechanismfor releasing the drug formulation from the drug storage element topermit the drug formulation to be transported into and through the atleast one channel of the at least one microneedle. The release mechanismmay utilize a mechanical force, heat, a chemical reaction, an electricfield, a magnetic field, a pressure field, ultrasonic energy, vacuum,pressure, or a combination thereof.

In one embodiment, the drug storage element includes a porous material,wherein the drug formulation is stored in pores of the porous material.In another embodiment, the drug storage element includes at least onesealed reservoir. In one variation of this embodiment, the devicefurther includes at least one puncturing barb extending from the firstsurface of the planar substrate, wherein the puncturing barb can be usedto puncture the sealed reservoir.

In a preferred embodiment, the device further includes a backingstructure and adhesive surface suitable for securing the device to theskin of a patient during administration of the drug formulation to thepatient.

In still another aspect, a method is provided for manufacturing amicroneedle array. In one embodiment, the method includes the steps offorming a substantially planar substrate having an array of spacedapertures therein; and forming a plurality of microneedles projecting atangle from the plane in which the planar substrate lies, themicroneedles having a base portion integrally connected to thesubstrate, a tip end portion distal to the base portion, and bodyportion therebetween, wherein at least one of the microneedles has atleast one channel extending substantially from the base portion throughat least a part of the body portion, the channel being open along atleast part of the body portion and in fluid communication with at leastone of the apertures in the substrate. In various embodiments, the stepof forming the plurality of microneedles comprises embossing, injectionmolding, casting, photochemical etching, electrochemical machining,electrical discharge machining, precision stamping, high-speed computernumerically controlled milling, Swiss screw machining, soft lithography,directional chemically assisted ion etching, or a combination thereof.

In a preferred embodiment, a method for manufacturing a microneedlearray is provided that includes the steps of providing a substantiallyplanar substrate material; forming a plurality of first apertures in thesubstrate material, wherein the interior surface of at least one of thefirst apertures defines a microneedle having a tip, a base, and a bodyportion therebetween; forming a plurality of second apertures in thesubstrate material, which at least one of the second apertures defines achannel located in the body portion of the microneedle; and bending themicroneedle near its base such that the tip projects out of the plane ofthe substrate material. In one embodiment, the step of forming the firstapertures, the forming the second apertures, or the forming both thefirst and second apertures includes removing portions of the substratematerial by a process comprises embossing, injection molding, casting,photochemical etching, electrochemical machining, electrical dischargemachining, precision stamping, high-speed computer numericallycontrolled milling, Swiss screw machining, soft lithography, directionalchemically assisted ion etching, or a combination thereof. In oneembodiment, the bending of the microneedle comprises direct or indirectapplication of a compressive force, heat, or a combination thereof, tothe microneedle and/or substrate.

In still another aspect, a method is provided for administering a drugto a patient in need thereof, which includes the steps of inserting intothe skin of the patient the microneedles of the microneedle devicesdescribed above, and causing the drug formulation to be transported fromthe drug storage element through the at least one channel of themicroneedle and through the stratum corneum of the skin. The transportof the drug formulation may be driven or assisted by capillary force,gravitational force, overpressure, vacuum, an electric field, a magneticfield, iontophoresis, a molecular concentration gradient, or acombination thereof.

In a further aspect, an applicator device is provided for applying amicroneedle array to skin. In one embodiment, the applicator deviceincludes a housing having a substantially planar application side and anopposed top side; a recess in the housing in which a drug deliverydevice that includes a microneedle array can be stored; and a button onthe top side of the housing, which button can be depressed to drive thedrug delivery device out of the recess with the microneedles orientedsubstantially perpendicular to the planar application side. In oneembodiment, the housing further comprises a roller disposed partially ina cavity on the planar application side of the housing.

In a preferred embodiment, the applicator device further includes one ormore of the drug delivery devices described above that includes amicroneedle array, wherein the device comprises a substantially planarsubstrate having an array of spaced apertures therein; a plurality ofmicroneedles projecting at angle from the plane in which the planarsubstrate lies, the microneedles having a base portion integrallyconnected to the substrate, a tip end portion distal to the baseportion, and body portion therebetween, wherein at least one of themicroneedles has at least one channel extending substantially from thebase portion through at least a part of the body portion, the channelbeing open along at least part of the body portion and in fluidcommunication with at least one of the apertures in the substrate; andat least one drug storage element, which contains a drug formulation,positioned adjacent to the planar substrate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an exploded, perspective view of one embodiment of atransdermal drug delivery device comprising an array of microneedles anda drug storage element.

FIG. 2 is a close-up view of part of one embodiment of a microneedlearray.

FIG. 3 is a plan view of one embodiment of an intermediate structureused in forming the microneedle array, wherein the microneedles of theintermediate structure are formed, and still are, in-plane with thesubstrate.

FIG. 4 is a close-up view of part of the intermediate microneedlestructure shown in FIG. 3.

FIGS. 5A-B are perspective views of one embodiment of an applicatordevice for applying a microneedle drug delivery device to a patient'sskin. FIG. 5A shows the application side, and FIG. 5B shows theactuation side.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Improved microneedle arrays and transdermal drug delivery devices havebeen developed. The microneedles of the array combine the advantages ofprior solid microneedles and prior microneedles with a central hollowbore, and avoid disadvantages of each. In particular, the presentmicroneedles advantageously have both a strong, small solid tip and achannel for drug to flow through the stratum corneum and into thepatient's lower skin tissues (e.g., epidermis, dermis, or subcutaneousskin layers) while the microneedle remains inserted in the patient'sskin during drug delivery. Consequently, drug delivery rates can bemaintained relatively constant because the created pores are kept openby the microneedles inserted into the patient's stratum corneum, andpain from insertion of the microneedles can be minimized since the tipportion of the microneedle can be made to have a smaller cross-sectionand sharper tip than conventional drug-coated solid microneedles orhollow microneedles with a central bore. In addition, mass transportusing the present microneedles can be increased relative to similarlydimensioned hollow or solid conventional microneedles. A still furtheradvantage of the present array design is that it may be fabricated usingrelatively easy and relatively inexpensive techniques, compared to thosetechniques required to make conventional hollow microneedles having acentral bore.

Applicator devices have also been developed for applying the microneedledrug delivery devices (e.g., patches) to a patient's skin.

As used herein, the terms “comprise,” “comprising,” include,” and“including” are intended to be open, non-limiting terms, unless thecontrary is expressly indicated.

Microneedle Array

The microneedle array comprises at least one substrate and a pluralityof microneedles projecting at an angle from the at least one substrate.In one embodiment, a microneedle array device is provided which includesa substantially planar substrate having an array of spaced aperturestherein. A plurality of microneedles project at angle from the plane inwhich the planar substrate lies. The microneedles have a base portionconnected to the substrate, a tip end portion distal to the baseportion, and body portion therebetween. At least one of the microneedleshas at least one channel extending substantially from the base portionthrough at least a part of the body portion, the channel being openalong at least part of the body portion and in fluid communication withat least one of the apertures in the substrate.

Generally, the microneedle can be in any elongated shape suitable forproviding the skin piercing and fluid conduit functions, with minimalpain to the patient. In various embodiments, the microneedle issubstantially cylindrical, wedge-shaped, cone-shaped, or triangular(e.g., blade-like). The cross-sectional shape (cut along a planeapproximately parallel to the planar substrate or approximatelyperpendicular to the longitudinal axis of the microneedle) of themicroneedle, or at least the portion of microneedle that is penetrableinto the skin, may take a variety of forms, including rectangular,square, oval, circular, diamond, triangular, or star-shaped. In apreferred embodiment, the microneedle has a substantially rectangularcross-sectional shape in a plane parallel to the substrate. In onespecific variation of this embodiment, the channel is open to twoopposing surfaces of the microneedle.

The tip portion of the microneedle is designed to pierce a biologicalbarrier, e.g., to pierce the stratum corneum of the skin of a patient,to form a conduit through which a drug formulation can be transportedinto the patient's tissue. To provide minimal pain to the patient, thetip portion of the microneedle should be sufficiently small and sharp toenable piercing and penetration of the skin with minimal pain. In apreferred embodiment, the tip end portion of the microneedle is taperedfrom the body portion toward the tip end, defining a point or apex atthe end of the microneedle. In one preferred variation, the channelterminates in the body portion of the microneedle and does not extendinto the tapered tip portion, such that microneedle tapers toward thetip at a point beyond the end of the channel. In various embodiments,the tapered tip portion may be in the form of an oblique angle at thetip, or a pyramidal or triangular shape.

The dimensions of the microneedles may vary depending on a variety offactors such as the type of drug to be delivered, the dosage of the drugto be delivered, and the desired penetration depth. Generally, themicroneedles are constructed to provide skin-piercing and fluid deliveryfunctions and thus will be designed to be sufficiently robust towithstand insertion into and withdrawal from the skin. Each microneedlehas a length of about 1 micrometer (μm) to about 5000 micrometers (μm).More preferably, each microneedle has a length of about 1 μm to about500 μm. Still more preferably, each microneedle has a length of about100 μm to about 500 μm. The penetration length of the microneedles intothe biological barrier is about 50 μm to about 200 μm. In addition, eachof the microneedles has a width of about 1 μm to about 500 μm.Furthermore, each microneedle has a thickness of about 1 μm to about 200μm. It will be understood by one skilled in the art that the width andthickness of the microneedle may vary along its length. For instance,the base portion may be wider (thicker) than the body portion, or thebody portion may have a slight taper approaching the tip portion.

The one or more channels in each microneedle provide a path for a drugformulation to flow from the apertures in the substrate through/into thebiological barrier at the site of piercing. The channel preferablyextends from the substrate toward the tip through a substantial portionof a length dimension of the microneedles. The channel does not extendall the way to the tip of the microneedle as a central bore would. Thechannel may comprise an opening through two surfaces of the microneedle.In alternate embodiments, the channel may comprise any shape suitable todeliver fluid proximal to the microneedle tip. For example, the channelmay comprise a groove on one surface of the microneedle that is onlyopen to the outside environment on one side of the microneedle. Inaddition, the channel may be dimensioned to provide a capillary force oreffect upon the fluid to be delivered such that the capillary effectdraws or wicks fluid into the base portion of the microneedle from thesubstrate aperture, through the body portion of the microneedle, andtoward the tip portion of the microneedle. In other embodiments, eachmicroneedle may have more than one channel, for example, two narrowerchannels in parallel.

The width of the channel may be constant along its length or may vary.The length of the channel will vary depending on a variety of factors,but will typically be about 50 to 99% of the length of the microneedle,and preferably is about 70 to 99% of the length of the microneedle.Nevertheless, it is possible that in certain embodiments the length ofthe channel will be between 1 to 50% of the length of the microneedle.As such, the length of the tip portion beyond the channel may vary, butusually is about 1 to 50% of the length of the microneedle, and moreusually is about 1 to 30% of the length of the microneedle. It will beappreciated by one skilled in the art that the width of the channel, thelength of the channel, and the length of the microneedle may be variedto increase or decrease the flow rate of the drug.

In one embodiment, the length of the at least one microneedle may bebetween 10 μm and 1000 μm, preferably between 100 μm and 500 μm. Inanother embodiment, the at least one microneedle has a maximum widthdimension of 500 μm. In one embodiment, the body portion of themicroneedle is rectangular with a centrally located channel extendingthrough the opposed longer sides of the body portion. In one particularembodiment, the rectangular body portion has a long side cross-sectionaldimension between 1 μm and 500 μm and a short side cross-sectionaldimension between 1 μm and 200 μm.

The apertures in the planar substrate may be in essentially any shape.In various embodiments, the apertures may be circular, semi-circular,oval, diamond, triangular, or a combination thereof. In a preferredembodiment, the apertures in the substrate are polygonal in shape, eachaperture being defined by three or more interior side surfaces in thesubstrate. In one embodiment, the base portion of the at least onemicroneedle includes a curved portion that extends from at least one ofthe interior side surfaces of the substrate. In one embodiment, aproximal end of the at least one channel extends to or into the at leastone of the interior side surfaces of the substrate.

In preferred embodiments, the substrate, the microneedles, or both, areformed of, or coated with, a biocompatible material. The microneedlesmay be formed from the substrate material, or alternatively, themicroneedles can include a material different from the substratematerial. Representative examples of suitable materials of constructioninclude metals and alloys such as stainless steels, palladium, titanium,and aluminum; plastics such as polyetherimide, polycarbonate,polyetheretherketone, polyimide, polymethylpentene, polyvinylidenefluoride, polyphenylsulfone, liquid crystalline polymer, polyethyleneterephthalate (PET), polyethylene terephthalate-glycol modified (PETG),polyimide, and polycarbonate; and ceramics such as silicon and glass.The material preferably is selected such that the microneedle is strongenough at its designed dimensions for the microneedle to effectivelypierce the biological barrier(s) of choice, without significant bendingor breaking of the microneedle. The microneedle and substrate materialsalso should be non-reactive with the drug formulation being deliveredthrough substrate apertures and microneedle channel(s). In a preferredembodiment, the microneedles and substrate consist of a metal or alloy.In another embodiment, the microneedles comprise a biocompatiblethermoplastic polymer.

The substrate, the microneedles, or both, optionally may further includesecondary materials of construction embedded therein or coated thereon.For example, microparticles, nanoparticles, fibers, fibrids, or otherparticulate materials may be included. Examples of such materialsinclude metals, carbon siliceous materials, glasses, and ceramics. Thesesecondary materials may enhance one or more physical or chemicalcharacteristics of the microneedle array. For example, the secondarymaterial may be insulating layer or may improve the flow or transport ofthe drug formulation through the apertures and channels of the array.Representative examples of suitable insulating materials includepolyethylene terephthalate (PET), polyethylene terephthalate-glycolmodified (PETG), polyimide, polycarbonate, polystyrene, silicon, silicondioxide, ceramic, glass, and the like. In a preferred embodiment,chemical vapor deposited silicon dioxide is used as an insulating layeron the microneedle array due to its hydrophilic nature, which mayfacilitate fluid delivery. In another embodiment, the channel of themicroneedle may include one or more agents to facilitate fluid flow. Forexample, one or more hydrophilic agents may be present on the interiorsurfaces defining the channel. Examples of such hydrophilic agentsinclude, but are not limited to, surfactants. Exemplary surfactantsinclude MESA, Triton, Macol, Tetronic, Silwet, Zonyl, and Pluronic.

The surface of the substrate that is in contact with the surface of thebiological barrier (e.g., the stratum corneum) may be coated, in wholeor in part, with a bonding substance that can secure the microneedlepatch to the biological barrier for an extended period of time, e.g.,for a duration required to release all of the drug formulation to thebiological barrier. Examples of such bonding agents include adhesivesand bioactive films, which are activated by pressure, heat, light (UV,visible, or laser), electric, magnetic fields, biochemical andelectrochemical reactions, or a combination thereof.

A representative embodiment of the microneedle array is shown in FIG. 1and FIG. 2. The microneedle array 12 includes a substantially planarsubstrate 14 and a plurality of microneedles 16 extending from theplanar substrate 14. The planar substrate 14 includes a plurality ofspaced apertures 13. The planar substrate 14 optionally may be coatedwith a bonding substance (not shown) to facilitate adhesion of themicroneedle array 12 to a surface of a biological barrier. Each of themicroneedles 16 has a base portion 15 connected to the planar substrate,a tip end portion 22 distal to the base portion 15, and a body portion17 therebetween. Each microneedle has an elongated channel 24 extendingfrom the base portion 15 through at least a part of the body portion 17.The channel 24 is open along the body portion, through two opposingsurfaces of the body portion, and the channel 24 is in fluidcommunication with aperture 13 in the planar substrate. The microneedles16, or at least the body and tip portions thereof, are substantiallyperpendicular to the planar substrate 14. The apertures 13 in thesubstrate are hexagonal and defined by interior side surfaces 19 in theplanar substrate. The base portion 15 of each of the microneedlesincludes a curved portion that is integrally connected to the planarsubstrate, extending from one of the interior side surfaces 19.

Microneedle Drug Delivery Device

In preferred embodiments, the microneedle array described in thepreceding section is part of a drug delivery device that includes a drugstorage element. The drug storage element is a means for containing adrug formulation for release to and through the microneedle array, fortransdermal administration of the formulation via the microneedle array.Preferably, the drug delivery device is in the form of a transdermaldrug delivery patch.

In a preferred embodiment, the drug storage element is positionedadjacent to the planar substrate. For example, the drug storage elementmay be attached to a first surface of the planar substrate, wherein thefirst surface is opposed to a second surface of the planar substratefrom which the microneedles project. In a preferred embodiment, the drugdelivery device is in the form of a patch that can be adhered to theskin during transdermal administration of a drug formulation through themicroneedle array. In one embodiment, the device, or patch, includes abacking structure and adhesive surface suitable for securing the deviceto the skin of a patient with the microneedles in an inserted positionin the skin.

In a preferred embodiment, the drug storage element has at least onesealed reservoir, which can be selectively punctured or otherwisebreached in a controlled manner to release a drug formulation containedtherein. In one embodiment, the drug storage element includes a porousmaterial, wherein the drug formulation is stored in pores of the porousmaterial. Representative examples of suitable porous materials includeopen cell polymeric foams, sheets/mats of woven or non-woven fibers,combinations thereof, and the like. In another example, the drug storageelement may be in the form of one or more substantially flat pouches,for example, made of two sheets of flexible thermoplastic polymericfilm, sealed along the edges to define a reservoir therebetween.

The “drug formulation” refers to essentially any therapeutic orprophylactic agent known in the art (e.g., an active pharmaceuticalingredient, or API), and typically includes one or more physiologicalacceptable carriers or excipients to facilitate transdermaladministration of the drug formulation. In one embodiment, the drugformulation is a fluid drug formulation, wherein the formulation canflow through apertures and channels in the microneedle array; it may bea solution, suspension, emulsion, or a combination thereof. In anotherembodiment, the drug formulation comprises a solid formulation, whereinthe transport of drug through apertures and channels in the microneedlearray involves diffusional transport mechanisms, with little or no bulkflow. The drug delivery device may include a drug formulation thatincludes a combination of liquid and solid components, wherein transportof the drug formulation involves both flow and mass diffusion.

The drug delivery device typically includes means for causing the drugformulation to be released from the drug storage element, permitting thedrug formulation to flow into or otherwise be transported through thechannel of the microneedle. The release typically is to and through theapertures in the planar substrate and thus to the base end of thechannel in the microneedle. A wide variety of release mechanisms forreleasing the drug formulation from the drug storage element can beenvisioned by those skilled in the art. These release mechanisms mayutilize a mechanical force, heat, a chemical reaction, an electricfield, a magnetic field, a pressure field, ultrasonic energy, vacuum,pressure, or a combination thereof. In one embodiment, the releasemechanism includes a means for applying a compressive force to a porousmaterial to expel the drug formulation from the pores in the porousmaterial. The means for applying a compressive force can be in the formof a spring-biased piston or button that can be manually depressed toapply a direct or leveraged force onto the back of the drug storageelement. The same force optionally may cause the microneedles to beinserted into the skin of a patient and/or cause a pressure-sensitiveadhesive surface on the device (e.g., on the periphery of a backingmaterial) to become adhered to the surface of the skin. In anotherembodiment, the drug delivery device includes at least one puncturingbarb extending from the surface of the planar substrate (opposite themicroneedle), wherein the puncturing barb can be used to puncture thesealed reservoir, e.g., upon application of a compressive force to thereservoir. This barb could be one or more microneedles bent in theopposite direction from the microneedles intended for skin insertion.

The flow of the drug formulation through the channels into thebiological barrier may be passive, e.g., the result of capillary andgravitational forces. Alternatively, the flow may be actively assisted.In one embodiment, the drug delivery device may include means foractively driving the drug formulation through the microneedle channelsand/or into the skin. For example, the flow of the drug formulationthrough the channels into the biological barrier may be aided byapplication of heat (e.g., generated by a series of microfabricatedresistors), an electric field, a magnetic field, a pressure field, aconcentration gradient, or any other physical force or energy. Theapplication of an electric field can comprise electrophoresis,iontophoresis, electroosmosis, electroporation, or the like. Theapplication of a magnetic field can comprise magnetophoresis or thelike. The application of a pressure field can comprise pumping, applyingultrasonic energy, applying vacuum, pressure, or the like.

FIG. 1 shows a transdermal drug delivery patch 10 comprising amicroneedle array 12 and a drug storage element 18, which is configuredto store a drug formulation therein for subsequent release to themicroneedle array.

Making the Microneedle Arrays

The microneedle arrays described herein can be made using or adapting avariety of fabrication techniques known in the art, depending upon theparticular materials of construction and the particularmicroneedle/array design selected. In one embodiment, the microneedlearray is made using one or more conventional microfabricationtechniques. The microneedles may be formed individually or the wholearray of microneedles and substrate may be formed in a single process.In a preferred embodiment, the microneedle arrays are formed in mass(i.e., commercial scale) quantities using inexpensive fabricationprocesses available in the art.

In one embodiment, the method for manufacturing a microneedle arrayincludes the steps of forming a substantially planar substrate having anarray of spaced apertures therein; and forming a plurality ofmicroneedles projecting at angle from the plane in which the planarsubstrate lies, the microneedles having a base portion integrallyconnected to the substrate, a tip end portion distal to the baseportion, and body portion therebetween, wherein at least one of themicroneedles has at least one channel extending substantially from thebase portion through at least a part of the body portion, the channelbeing open along at least part of the body portion and in fluidcommunication with at least one of the apertures in the substrate. Invarious embodiments, the step of forming the plurality of microneedlesincludes embossing, injection molding, casting, photochemical etching,electrochemical machining, electrical discharge machining, precisionstamping, high-speed computer numerically controlled milling, Swissscrew machining, soft lithography, directional chemically assisted ionetching, or a combination thereof.

In one particular embodiment, the method for manufacturing a microneedlearray includes the steps of providing a substantially planar substratematerial; forming a plurality of first apertures in the substratematerial, wherein the interior surface of at least one of the firstapertures defines a microneedle having a tip, a base, and a body portiontherebetween; forming a plurality of second apertures in the substratematerial, which at least one of the second apertures defines a channellocated in the body portion of the microneedle; and bending themicroneedle near its base such that the tip projects out of the plane ofthe substrate material. In particular variations of this embodiment, theforming of the first apertures, the forming of the second apertures, orthe forming of both the first and second apertures includes removingportions of the substrate material, proximate to each of the pluralityof microneedles to shape each microneedle. This process may includeembossing, injection molding, casting, photochemical etching,electrochemical machining, electrical discharge machining, precisionstamping, high-speed computer numerically controlled milling, Swissscrew machining, soft lithography, directional chemically assisted ionetching, or a combination thereof. In one embodiment, the step ofbending the microneedle comprises direct or indirect application of acompressive force, heat, or a combination thereof, to the microneedleand/or substrate.

The forming of the microneedles may include forming the microneedlesin-plane with the substrate and then bending the plurality ofmicroneedles out-of-plane with the substrate, for example, to a positionsubstantially perpendicular to the planar substrate surface.Alternatively, the microneedles may be fabricated originallyout-of-plane with the substrate (i.e., with no intermediate in-planestructure). For example, directional chemically assisted ion etching canbe used to fabricate the microneedles that are initially out-of-planewith the substrate. These various microneedle fabrication options allowthe microneedle arrays to be fabricated from flexible substrates and/orinflexible substrates.

In a preferred embodiment, microneedles may be formed in-plane orout-of-plane with the substrate using a microreplication technique knownin the art. Representative examples of suitable microreplicationtechniques include embossing, injection molding and casting processes.Such microreplication techniques, and in particular embossingtechniques, may provide low cost manufacturing and also mayadvantageously enable the tip of the microneedle to be extremely small(near infinitesimally small cross-sectional area) and sharp.Furthermore, embossing techniques allow precise, consistent fabricationof the microneedles.

In a preferred embodiment, an embossing technique is used. In oneprocess using an embossing technique, a planar substrate material, suchas a suitable thermoplastic precursor material, is placed into anembossing apparatus, where such an apparatus includes a mold havingfeatures of a microneedle array as described herein. (The mold may havea negative image of the features of the microneedles.) The precursormaterial is then compressed by the mold under heat and a suitablecompression force. In one embodiment, the planar substrate material hasa thickness in the range of about 25 μm to about 650 μm, preferably fromabout 50 μm to about 625 μm, and more preferably from about 75 μm toabout 600 μm. In one embodiment, the substrate material is heatedtemperature in the range of about 20° C. to 1500° C., preferably fromabout 100° C. to 1000° C., more preferably from about 200° C. to 500° C.The heat is usually applied to the substrate material for about 0.1seconds to 1000 seconds, preferably for about 0.1 seconds to 100seconds, and more preferably about 0.1 seconds to 10 seconds. Thecompression force may range from about 1 GPa to 50 GPa, preferably fromabout 10 GPa to 40 GPa, and more preferably from about 20 GPa to 30 GPa.The compression force may be applied for about 0.01 seconds to 100seconds, preferably for about 0.01 seconds to 10 seconds, and morepreferably about 0.01 seconds to 1 second. The heat and compressionforce may be applied at the same time or different times. After thesubstrate material is cooled, it is removed from the embossingapparatus, yielding an embossed array of microneedles, which may bein-plane or out-of-plane. If the microneedles of the embossed array arein-plane with the substrate, then the microneedles subsequently aresubjected to a bending step to fix them into an out-of-plane orientationrelative to the substrate.

The step of bending in-plane microneedles of an intermediate structureinto an out-of-plane position to form a microneedle array can be doneusing a variety of different methods, to effect application of a director indirect force that causes plastic and/or elastic deformation of themicroneedles, preferably limited to the base portion thereof. In oneexample, the bending of the microneedles out-of-plane with the substratemay be facilitated by the use of a mold (e.g., a metal mold) havingprotrusions corresponding to the number and position of the microneedlesin the intermediate structure, whereby the mold can be engaged (e.g.,compressed) with the intermediate structure, the compressive forcebetween the protrusions and the microneedles causing all of themicroneedles to bend (at their base portions) simultaneouslyout-of-plane. In another example, the microneedle array can be pressedbetween a thick elastic film (e.g., rubber or polyurethane) and a moldhaving cavities corresponding to the number and position of themicroneedles to bend the microneedles out-of-plane with the substratesimultaneously. The compressive force squeezes the thick elastic filminto the cavities on the opposite side of the substrate, and the thickelastic film consequently bends the microneedles out-of-plane with thesubstrate and into the cavities.

Heat and/or various auxiliary pressures can be used in conjunction withthe bending force to facilitate the bending of the microneedles. Forexample, a heated high-speed liquid or gas can be flowed in a directionsubstantially perpendicular to the plane of the substrate comprisingplastic microneedles. The plastic microneedles are heated by the flowingfluid, undergo a plastic transition, and then are bent out-of plane withthe substrate by the force of the high-speed fluid. In otherembodiments, the step of bending the in-plane microneedles may includedirectly or indirectly applying an electric field or a magnetic field tomicroneedles.

FIG. 3 and FIG. 4 illustrate one embodiment of an intermediatemicroneedle structure 30. Structure 30 includes a planar substrate 34and a plurality of microneedles 36 positioned in apertures 46 in theplanar substrate 34. The microneedles lie in the plane of the planarsubstrate. Each microneedle 36 has a base portion 37, a tip end portion42, and a body portion 38 therebetween. Each microneedle 36 also has anelongated channel 44 in the base portion and body portion of eachmicroneedle. To make a microneedle array for drug delivery from thisintermediate structure, the microneedles 36 will be bent out-of-planewith the planar substrate 34.

The microneedle arrays and drug storage elements can be made separatelyand then assembled using known techniques for connecting conventionalmicroneedle arrays to a drug storage element, which preferably is donein an aseptic or sterile environment.

Drug Device Applicator and Use of the Microneedle Array Devices

Drug delivery devices comprising the microneedle arrays described hereinpreferably are used to deliver a drug formulation across a biologicalbarrier. The biological barrier preferably is human or other mammalianskin, although other tissue surfaces may be envisioned. In a typicaluse, the drug formulation is released from the drug storage element, itflows to the microneedle array, where it passes through the apertures inthe planar substrate of the array and then enters the channels of themicroneedles at the base portions of the microneedles. The drugformulation then is transported through the channel, traversing thestratum corneum and then entering the epidermis, dermis, and/orsubcutaneous skin tissues. After administration of the drug formulationis complete, the microneedles are removed from the skin.

In a preferred embodiment, a method of administering a drug to a patientin need thereof includes the steps of inserting into the skin of thepatient the microneedles of a drug delivery device that has a drugstorage element containing a drug formulation, and then causing the drugformulation to be transported from the drug storage element, into andthrough at least one channel of at least one of the microneedle, andthrough the stratum corneum of the skin. The transport of the drugformulation can be passively or actively assisted. In variousembodiments, the drug formulation is transported under the influence orassistance of capillary forces, gravitational forces, overpressure,vacuum, an electric field, a magnetic field, iontophoresis, a molecularconcentration gradient, or a combination thereof. One skilled in the artcan utilize or readily adapt any of these means using technology knownin the art.

The microneedles of the drug delivery device can be inserted into theskin by a variety of means, including direct manual application or withthe aid of an applicator device to insure uniform and proper microneedlepenetration, consistently within a single array and across differentarrays. The applicator device may be completely mechanical or it may beelectromechanical. The applicator device may include pressure sensors incommunication with an electronically controlled release mechanism, toinsure that a drug delivery device is applied to the skin with thedesired force each time. Optionally, the applicator device may includehardware, software, and power source components to provide heat,electrical field, magnetic field, pressure, or other drug deliveryassistance means known in the art. The applicator device may include oneor more rollers for use in applying an even pressure to the drugdelivery patch to ensure that it is completely secured to the skin. Theroller may, for example, further secure a pressure sensitive adhesivesurface around the periphery of the patch.

One example of a simple applicator device is shown in FIGS. 5A-B.Applicator device 50 includes a rigid housing 51 having a substantiallyplanar application side 56 and an opposed actuation (top) side 58; arecess 52 in the housing in which a drug delivery device (i.e., a patch)60 that includes a microneedle array 62 is disposed; and a button 54 onthe top side of the housing 51. The button can be depressed to drive thedrug delivery device 60 out of the recess 52 to and to drive themicroneedles 62 into the skin (piercing the stratum corneum), when theapplication side is placed against the skin of a patient at the site fortransdermal administration of the drug formulation. The housing furtherincludes a roller 64 disposed partially in a cavity 66 on theapplication side of the housing. The roller 64 is used for completelyinserting the microneedles 62 into the biological barrier as well as forestablishing and facilitating a secure bond between the drug deliverydevice 60 and the surface of the biological barrier. The action ofdepressing the button 54 followed by application of the roller 64 alsosupplies a compressive force to the drug storage element (not shown)causing the drug formulation to be released from the drug storageelement to the apertures and channels of the microneedle array. Theroller 64 can also generate pressure, heat, light (e.g., UV, visible, orlaser), electric, magnetic fields, biochemical and electrochemicalreactions, or a combination thereof aimed to activate the bondingsubstance applied on the surface of the drug delivery device 60 whichcan hold the drug delivery device 60 attached to the biological barrier(not shown) for an extended period of time.

Publications cited herein are incorporated by reference. The foregoingdescription of various embodiments of the present invention is presentedfor purposes of illustration and description. The description is notintended to be exhaustive or to limit the invention to the precise formdisclosed. The embodiments were chosen and described in order to bestillustrate the principles of the invention and its practical applicationto thereby enable one of ordinary skill in the art to best utilize theinvention and various embodiments with various modifications as aresuited to the particular use contemplated. Modifications and variationsof the methods and devices described herein will be obvious to thoseskilled in the art from the foregoing detailed description. Suchmodifications and variations are intended to come within the scope ofthe appended claims.

I claim:
 1. A method for manufacturing a microneedle array comprisingproviding a substantially planar substrate material; forming a pluralityof first apertures in the substrate material, wherein the interiorsurface of at least one of the first apertures defines a microneedlehaving a tip, a base, and a body portion therebetween; forming aplurality of second apertures in the substrate material, each of thesecond apertures defining an elongated channel located in the bodyportion of the microneedle; and bending the microneedle near its basesuch that the tip and body portion project out of the plane of thesubstrate material, wherein the tip of the microneedle is tapered, thebody portion is rectangular, and the channel extends through 50% to 99%of the length of the microneedle substantially from the planarsubstrate, through the base, and through at least a part of the bodyportion.
 2. The method of claim 1, wherein the bending of themicroneedle comprises direct or indirect application of a compressiveforce, heat, or a combination thereof, to the microneedle and/orsubstrate material.
 3. The method of claim 1, wherein the substratematerial and the microneedle comprise stainless steel or anotherbiocompatible metal.
 4. The method of claim 1, wherein the firstapertures in the substrate material are polygonal in shape, eachaperture being defined by three or more interior side surfaces in thesubstrate material.
 5. The method of claim 1, wherein the microneedlehas a length between 1 μm and 5000 μm.
 6. The method of claim 1, whereinthe microneedle has a length between 10 μm and 1000 μm.
 7. The method ofclaim 1, wherein the microneedle has a width between 1 μm and 500 μm. 8.The method of claim 1, wherein the microneedle has a thickness between 1μm and 200 μm.
 9. The method of claim 1, wherein the steps of formingthe first and second apertures comprise embossing, injection molding,casting, photochemical etching, electrochemical machining, electricaldischarge machining, precision stamping, high-speed computer numericallycontrolled milling, Swiss screw machining, soft lithography, directionalchemically assisted ion etching, or a combination thereof.